1. Field of the Invention
The invention relates to the chemical synthesis of taxol, taxol intermediates, taxol precursors and novel taxol related compounds accessible through these precursors. Also described are pharmaceutical compositions and methods of use of the new compounds that have taxol-like activity.
2. Description of Related Art
The synthesis of the diterpene alkaloid taxol has been a popular target for total synthesis for the past ten years; however, it is only recently that the need for a total synthesis has taken on a new urgency in view of its medical importance in breast cancer treatment (Time, 1991) and more recently a possible treatment in kidney disease (Pharmaceuticals & Biotech Daily, 1994). Taxol is in phase II/phase Ill clinical trials and is showing extremely promising activity, particularly against ovarian, breast and lung cancers (Rowinsky, et al., 1990). Taxol has several advantages over other antitumor agents currently in use, including its relative lack of toxicity compared to other antitumor agents such as vinblastine and vincristine. Consequently, taxol has become the focus of a large number of antitumor programs both in academia and in the pharmaceutical industry (Klingston, et al., 1990; Winkleer, 1992; Swindell, 1991). Unfortunately, this effort, intended to explore the full range of tumor response to taxol chemtherapy, is severely limited by the scarcity of taxol itself.
Taxol is isolated from the North American Yew tree but only in very small amounts, requiring a time-consuming purification. The yew tree is an environmentally protected species and cannot be considered a permanent source of taxol. Even if this were not the case, the total yew tree population is estimated to yield only enough taxol for approximately one year of clinical evaluation.
Even if Taxol supplies were abundant, it has become apparent that potency of the drug is relatively low so that there is a particular need to obtain quantities sufficient to develop more active derivatives and analogs of this promising drug. French researchers have recently claimed that certain derivatives of taxol such as taxotere are more potent than the parent (Mangatal, et al., 1989; Colin, et al., 1988).
Therapeutic protocols presently require dose levels of 500 mg per patient, making it even more imperative to develop alternate sources of the drug or to devise an efficient chemical synthesis. Current supplies are inadequate to afford treatment to all patients for whom this drug is indicated.
There is therefore a need to provide a chemical synthesis of taxol efficient enough to supply large quantities (&gt;100 kilos), and flexible enough to provide analogs in order to explore structure activity relationships (SAR). Such structure activity relationships for taxol and taxotere are the subject of current research (see, for example, Ojima, et al., 1994). Analogs and derivatives of taxol offer potential for more effective treatment of breast cancer with the goal of developing more selectivity and higher potency. Additionally, as with most cancer therapy, resistance to treatment is usually encountered, creating a need for second and third generation derivatives of the active parent compound.
Currently, research groups attempting to develop a total or partial synthesis of taxol, while making some progress, have developed multistep syntheses on the order of thirty to forty steps (Borman, 1991). This is far too long to be of any real practical commercial use, as anything more than 25 steps is not considered to be practical (Science, 1994). The synthesis of taxol should be no more than about twenty steps, and it is essential that the synthesis be enantiospecific.
The synthesis of taxol is, however, complicated by its different functional groups, making it difficult to predict the effect of modifications in one part of the molecule on other positions. Recently, total synthesis of taxol has been reported (Holton, et al., 1994; Nicolaou, et al., 1994). While of scientific significance, these syntheses do not appear to be commercially viable routes to taxol because the number of synthetic steps is quite high and because overall yields are low (Science, 1994).
It is therefore desirable to develop a simple, efficient synthetic route to taxol. Intermediates along the route as well as the end product will provide compounds so as to be able to determine the effect of structure activity relationships. This will lead to improvements on the natural form of taxol and will provide a rational approach in reducing toxicity and increasing efficacy.